(1) Field of the Invention
This invention relates to a novel chemical synthesis of pyrrolo[2,1-c][1,4]benzodiazepin-5-one antitumor antibiotics previously prepared only by fermentation of a strain of Streptomyces designated Streptomyces sp. strain J576-99 (ATCC 39143).
(2) Description of the Prior Art
The present invention relates to the total synthesis of two pyrrolobenzodiazepine antibiotics having the formula ##STR1## These antitumor antibiotics have been disclosed in U.S. application Ser. No. 401,469 filed July 26, 1982 as being isolated from the fermentation broth of Streptomyces sp. strain J576-99 (ATCC 39143). The BBM-2040 antibiotic may be obtained from the fermentation broth in two different forms, A and B, according to the isolation procedure employed. The BBM-2040 antibiotics inhibit the activity of various gram-positive and acid-fast bacteria and also inhibit the growth of mammalian tumors such as P388 leukemia in mice.
The epimers of BBM-2040A and B have been disclosed in Symposium Papers of the 24th Symposium on the Chemistry of Natural Products (Osaka, Japan, Oct. 13-16, 1981): Paper #72, pp 552-559. Compounds 31b and 32b in this paper were prepared by a total synthesis procedure and have the structures ##STR2## They may be differentiated from BBM-2040A and B in the configuration of the C-2 hydroxy group, i.e. BBM-2040A and B have the C-2 hydroxy group in the .alpha.-configuration while the corresponding 31b and 32b diastereoisomers have the .beta.-configuration at the C-2 hydroxy group. It has been found that the .beta.-hydroxy isomers described in the reference are essentially devoid of antitumor activity in the P388 mouse leukemia test while the .alpha.-hydroxy isomers have a marked activity against P388 mouse leukemia in this same screening test.
The BBM-2040 antibiotics are members of the anthramycin-neothramycin group of antibiotics. Several members of this group have been disclosed in the scientific literature.
The antitumor antibiotics, neothramycin A and neothramycin B, are disclosed in J. Antibiotics 29(1): 93-96 (1976) and J. Antibiotics 30(4): 340-343 (1977) ashaving the structures
______________________________________ ##STR3## R.sub.1 R.sub.2 ______________________________________ neothramycin A H OH neothramycin B OH H ______________________________________
The antibiotic BBM-2040B may be structurally differentiated from the neothramycins in the position of its hydroxyl group.
The antitumor antibiotic, tomaymycin, is disclosed in J. Antibiotics 25(8): 437-444 (1972) and Chem. Pharm. Bull. 19(11): 2289-2293 (1971) as being obtained by fermentation of Streptomyces achromogenes var. tomaymyceticus. Tomaymycin, which has the structure ##STR4## may be differentiated from BBM-2040A by the presence of the ethylidene group at the C-2 position.
The antitumor antibiotic, pretomaymycin, is disclosed in J. Antibiotics 25: 437 (1972) as having the structure ##STR5## Pretomaymycin may be differentiated from BBM-2040B by the ethylidene group at the C-2 position.
The antitumor antibiotic, oxotomaymycin, having the formula ##STR6## is disclosed in Chem. Pharm. Bull. 19: 2289 (1971). Oxotomaymycin differs from the BBM-2040 antibiotics in the presence of the 2-ethylidene group and the presence of the carbonyl group at C-11.
Among the members of the anthramycin group of antitumor antibiotics are anthramycin having the formula ##STR7## which is disclosed in J. Am. Chem. Soc. 87: 5791 (1965), mazethramycin having the formula ##STR8## which is disclosed in J. Antibiotics 33(6): 665-667 (1980) and sibiromycin of the formula ##STR9## which is disclosed in J. Antibiotics 27(11): 866-873 (1974) and J. Antibiotics 25(11): 668-673 (1972).
An extensive comparison of anthramycin, tomaymycin and sibiromycin is found in J. Antibiotics 30(5): 349-370 (1977).
Procedures for total synthesis of anthramycin are disclosed in J. Am. Chem. Soc. 90: 5641-5643 (1968) and in J. Chem. Soc., Chem. Commun., 741-742 (1982).
Chem. Pharm. Bull 19: 2289-2293 (1971) discloses the reaction steps ##STR10## The above steps are substantially the same as steps (1), (2), (3) and (5) of the present process except that an ethyl group is used to protect the C-8 hydroxyl group. Such a protecting group is not readily removable and the resulting process, therefore, is not suitable for use in preparing the BBM-2040 antibiotics. This reference makes no suggestion of further converting the amide product to a carbinolamine product such as BBM-2040A.